Although the arterial pressure of a large percentage of hypertensive patients is sensitive to a high sodium diet, the mechanisms underlying the progression of hypertension and end-stage renal disease in salt-sensitive hypertension are unknown. Recent studies in humans and in animal models of salt- sensitive hypertension indicate that an increase in oxidative stress is associated with the progressive elevation in arterial pressure and reduction in renal function. One of the mediators in causing increased superoxide (O2.-) release in salt-sensitive hypertension is increased endothelin levels which may stimulate NADPH oxidase formation. Studies derived from our previous Program project grant have shown that the Dahl salt-sensitive rat has elevated oxidative stress and endothelin, decreased renal superoxide dismutase (SOD) levels and progressive renal damage. After a 3 week-high Na diet, Dahl S rats experience increased urinary excretion of isoprostanes, increased O2.- release from the kidneys, increased arterial pressure and urinary protein excretion, mild increases in the percentage of glomeruli with glomerulosclerosis and no change in GFR or renal plasma flow. In contrast, after a 5 week-high Na diet, O2.- release from the kidneys is elevated, arterial pressure and urinary protein excretion are much higher than in the S rats on 3 weeks of high Na, glomerular damage is significant, and GFR and renal plasma flow are markedly decreased. Preliminary studies from our laboratory also indicate that vitamin E+C administration decreases renal O2.- release and arterial pressure, prevents the decreases in GFR and renal plasma flow, decreases urinary protein excretion and markedly decreases renal damage. In the 5-week S rats, renal SOD activity is decreased, and the antioxidants, allopurinol which inhibits XO, and Tempol, a SOD mimetic, both decreased the renal O2.- release in the 5-week S high Na rats. In addition, in S high Na rats, a 5-week administration of N-acetylcysteine, which increases glutathione levels, decreased arterial pressure, increased GFR and renal plasma flow and decreased urinary protein excretion. Based on these preliminary findings we propose the central hypothesis that excessive production of reactive oxygen species by specific oxidases in the kidney and or deficiencies in renal antioxidant mechanisms play an important role in the progression of hypertension and renal damage in Dahl salt-sensitive rats. The following specific aims will test this central hypothesis: 1) To test the hypothesis that increases in reactive oxygen species mediate the progressive increases in arterial pressure, the decreases in GFR and renal plasma flow, and the increase in renal damage that occur in Dahl salt-sensitive hypertension. 2) To test the hypothesis that increases in xanthine oxidase activity in the kidney play an important role in the increases in renal O2.- release and the abnormalities in cardiovascular and renal function in Dahl salt-sensitive hypertension. 3) To test the hypothesis that increases in NADPH oxidase activity in the kidney play an important role in the increases in renal O2.- release and the abnormalities in cardiovascular and renal function in Dahl salt-sensitive hypertension. 4) To test the hypothesis that endothelin plays an important role in the increases in renal O2.- and the reduction in renal function via stimulation of NADPH oxidase in Dahl salt-sensitive hypertension. 5) To test the hypothesis that decreases in SOD activity in the kidney play an important role in the increases in renal O2.- release and the abnormalities in cardiovascular and renal function in Dahl salt-sensitive hypertension. 6) To test the hypothesis that decreases in renal glutathione levels play an important role in the increases in renal release of reactive oxygen species and the abnormalities in cardiovascular and renal function in Dahl salt-sensitive hypertension.